Decarboxylative Annulation of α-Amino Acids with β-Ketoaldehydes

Article abstract of DOI:10.1021/acs.orglett.7b03721

Indolizidine and quinolizidine derivatives are readily assembled from l-proline or (±)-pipecolic acid and β-ketoaldehydes via a decarboxylative annulation process. These reactions are promoted by acetic acid and involve azomethine ylides as reactive intermediates.

Full text of DOI:10.1021/acs.orglett.7b03721

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Decarboxylative Annulation of α‑Amino Acids with β‑Ketoaldehydes
Anirudra Paul,†,‡ N. R. Thimmegowda,† Thiago Galani Cruz,† and Daniel Seidel*,†,‡
†Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854,
United States
‡Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, Florida 32611, United States
S
* Supporting Information
ABSTRACT: Indolizidine and quinolizidine derivatives are readily
assembled from L-proline or ( )-pipecolic acid and β-ketoaldehydes via
a decarboxylative annulation process. These reactions are promoted by
acetic acid and involve azomethine ylides as reactive intermediates.
n the course of our studies on the development of redox-
decarboxylative condensation, can undergo a range of non-
pericyclic transformations.5−8 Two main types of reactions have
been identified, decarboxylative three-component coupling
reactions and decarboxylative annulations.5 The majority of
these reactions are limited to nonenolizable aldehydes and
ketones. An early example of a decarboxylative annulation with
an enolizable species is the reaction of L-proline with an indole
containing α-ketoester (eq 2).5f To our knowledge, decarbox-
ylative annulations with enolizable aldehydes have thus far only
been achieved with 4-nitrobutyraldehydes (eq 3).5r
I
neutral procedures for the C−H functionalization of
amines,1 we recently established a method for the synthesis
of polycyclic amines via redox-neutral annulation of cyclic
amines with β-ketoaldehydes.1f This method was applied to the
synthesis of the commercial drug tetrabenazine (eq 1). A
The feasibility of a decarboxylative annulation of L-proline
with β-ketoaldehydes was first evaluated with nonenolizable
substrate 1a (Table 1).9 Only insignificant amounts of the
desired product 2a were obtained upon heating 1a under reflux
in xylenes in the presence of 4 equiv of L-proline (entry 1).
a
Table 1. Reaction Development
b
entry
x
AcOH (equiv)
solvent
time (h)
yield (%)
1
2
3
4
5
6
7
8
9
4
4
4
4
4
4
4
8
2
4
4
xylenes
xylenes
xylenes
xylenes
xylenes
PhMe
0 + 2
0 + 2
6
12
21
52
51
44
75
48
26
40
18
5
10
0 + 2
current limitation of this chemistry is the requirement for
relatively activated amines such as 1,2,3,4-tetrahydroisoquino-
line and tryptoline. Substrates such as pyrrolidine and
piperidine, which would provide access to substituted
indolizidines and quinolizidines, core structures of a significant
number of natural products,2 failed to undergo annulation with
β-ketoaldehydes under a range of conditions. Here, we report a
decarboxylative annulation approach to the synthesis of
indolizidine and quinolizidine derivatives from L-proline/
( )-pipecolic acid and β-ketoaldehydes.
Amino acids formally derived from secondary amines, such as
proline, sarcosine, and pipecolic acid, have long been known to
undergo the formation of azomethine ylides upon decarbox-
ylative condensation with an aldehyde.3 The chemistry of these
dipolar intermediates is dominated by pericyclic reactions.4 We
and others have shown that azomethine ylides, obtained via
20
0 + 2
20
0 + 15
0 + 2
20
20
xylenes
xylenes
xylenes
xylenes
AcOH
15 + 2
15 + 2
15 + 2
15 + 2
15 + 2
20
20
c
10
20
11
neat
a
Reactions were performed with 0.5 mmol of ketoaldehyde 1. Yields
are isolated yields of chromatographically purified compounds.
Addition time for 1 + additional reaction time after completed
addition. Reaction was performed in the absence of 4 Å MS.
b
c
Received: November 30, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03721
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Upon addition of 5 equiv of acetic acid, 2a was obtained in 12%
yield (entry 2). The yield of 2a increased to 21% with 10 equiv
of acetic acid (entry 3) and to 52% with 20 equiv of acetic acid
(entry 4). Prolonging the reaction time from 2 to 15 h had no
discernible effect on reaction yield (entry 5). A change of
solvent from xylenes to toluene resulted in a lower yield (entry
6). Slow addition of β-ketoaldehyde 1a led to a marked increase
in reaction efficiency and enabled the isolation of product 2a in
75% yield (entry 7). An increase or decrease in the amount of
L-proline had a detrimental effect on reaction yields (entries 8
and 9). Significant reduction in yield to 40% was noted in the
absence of molecular sieves (entry 10). The utilization of acetic
acid as the sole reaction medium provided unfavorable results
(entry 11). It should be noted that, in all cases, complete
consumption of β-ketoaldehyde 1a was observed.
annulations with a range of nonenolizable β-ketoaldehydes 1.
The corresponding products were obtained in moderate to
good yields. β-Ketoaldehydes 1 bearing a phenyl or methyl
substituent in the 4-position provided the corresponding
indolizidine and quinolizidine products as essentially single
diastereomers. Gratifyingly, the standard reaction conditions
were applicable to a number of enolizable β-ketoaldehydes 1.
Different substitution patterns were realized, and products were
obtained with reasonable levels of diastereoselectivity.
All annulation products contain a ketone moiety, offering
numerous possibilities for further modification. For instance,
reduction of indolizidine 2a with sodium borohydride in
methanol provided amino alcohol 3 in highly diastereoselective
fashion and 85% yield (eq 4).
The scope of the decarboxylative annulation reaction of β-
ketoaldehydes 1 was explored as summarized in Scheme 1,
utilizing the optimized conditions (Table 1, entry 7). L-Proline
and ( )-pipecolic acid readily underwent decarboxylative
A proposed mechanism for the decarboxylative annulation
reaction of β-ketoaldehyde 1a with L-proline is shown in
Scheme 2. Decarboxylative condensation of 1a with L-proline
a
Scheme 1. Scope of the Decarboxylative Annulation
Scheme 2. Proposed Mechanism
gives rise to azomethine ylide 4, which is thought to be a key
intermediate.4 In analogy to the established mechanism for the
annulation of amines with 4-nitrobutyraldehydes,1b addition of
acetic acid to 4 likely results in the formation of N,O-acetal 5.
Intramolecular proton transfer could then lead to the formation
of zwitterion 6, followed by elimination of acetic acid to provide
zwitterion 7. The latter undergoes a Mannich ring closure to
give final product 2a. A potential and unproductive albeit
ultimately inconsequential side reaction involves addition of
acetic acid to azomethine ylide 4 with formation of N,O-acetal
8, a regioisomer of 5. However, N,O-acetal 8 could reengage L-
proline to ultimately form product 2a while generating
pyrrolidine as a byproduct. This ability of the system to correct
for the “wrong” regiochemistry was recently demonstrated in
the context of the decarboxylative Strecker reaction.5i
Consistent with this notion, an excess of the amino acid
reaction partner is typically beneficial in decarboxylative
annulations. In regard to product diastereoselectivity, stereo-
genic centers in α-position of the ketone can likely undergo
epimerization under the reaction conditions. In addition, the
Mannich step has previously been shown to be reversible.1f
Consequently, the diastereomeric ratios of the annulation
products likely reflect their corresponding thermodynamic
stabilities.
a
Reactions were performed on a 0.5 mmol scale. All yields correspond
b
to isolated yields of purified products. Due to the limited solubility of
the corresponding β-ketoaldehyde starting material in xylenes, both
starting materials were mixed directly and allowed to react for 15 h.
B
DOI: 10.1021/acs.orglett.7b03721
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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In summary, we have achieved decarboxylative annulations of
L-proline and ( )-pipecolic acid with enolizable and non-
enolizable β-ketoaldehydes. This method provides rapid access
to decorated indolizidines and quinolizidines.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03721.
Experimental procedures and characterization data
(PDF)
Accession Codes
CCDC 1557923−1557924 and 1581830 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, or by emailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: seidel@chem.ufl.edu.
ORCID
Daniel Seidel: 0000-0001-6725-111X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the NIH-NIGMS (R01GM101389) is
gratefully acknowledged. We thank Dr. Tom Emge (Rutgers
University) for crystallographic analysis. N.R.T. acknowledges
UGC, New Delhi, for a Raman Postdoctoral Fellowship.
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DOI: 10.1021/acs.orglett.7b03721
Org. Lett. XXXX, XXX, XXX−XXX